The present invention relates to certain urea derivatives that are inhibitors of CCR-3 receptor activity, methods for preparing these compounds, pharmaceutical compositions containing such compounds and methods for their use.
Chemokines are chemotactic cytokines that are produced by a variety of cells to attract leukocytes to sites of inflammation or lymphoid tissue. CCR-3 is a chemokine receptor that is expressed in a variety of cells, including, but not limited to, eosinophils, basophils, T cells and dendritic cells. See Ponath, P. D. et al., J. Exp. Med. (1996) 183, 2437-2448; Yamada, H. et al., Biochem. Biophys. Res. Comm. (1997) 231, 365-368; Sallusto, F. et al., Science (1997) 277, 2005-2007; Sato, K. et al., Blood (1999) 93, 34-42. CCR-3 is also known as a co-receptor to HIV virus infection. See He, J. et al., Nature (1997) 385, 645-649. Several chemokines including eotaxin, eotaxin-2, RANTES, MCP-2, MCP-3, MCP4 bind to CCR-3 and activate cell functions such as intracellular Ca2+ mobilization, chemotactic response, superoxide anion generation and cell aggregation. See Forssmann, U. et al., J. Exp. Med. (1997) 185, 2171-2176; Heath, H. et al., J. Clin. Invest. (1997) 99, 178-184; Uguccioni, M. et al., J. Exp. Med. (1996) 183, 2379-2384; Tenscher, K. et al., Blood (1996) 88, 3195-3199; Sato, K. et al., Blood (1999) 93, 34-42. In particular, eotaxin exhibits a potent and specific chemotactic activity for eosinophils via binding to CCR-3, in vitro and in vivo. See Ponath, P. D. et al., J. Clin. Invest. (1996) 97, 604-612.
Tissue eosinophilia is observed in a number of pathological conditions such as asthma, rhinitis, eczema, inflammatory bowel diseases and parasitic infections. See Bousquest J. et al., N. Eng. J. Med. 323, 1033-1039; Middleton, Jr., E. et al., Chapter 42, Allergy Principles and Practice 4th ed. vol.2 Mosby-Year Book, Inc. 1993 U.S.A. In asthma, the airways of patients are infiltrated by a large numbers of eosinophils, and eotaxin production in bronchial mucosa and bronchoalveolar lavage (BALF) is increased. Several studies have suggested a strong correlation between the number of eosinophils in BALF, the eotaxin level in BALF and the clinical parameters of disease severity. See Walker, C. et al., J. Allergy Clin. Immunol. (1991) 88, 935-942; Ying, S. et al., Eur. J. Immunol. (1997) 27 3507-3516. Furthermore, pretreatment with a CCR-3-antibody has been shown to block chemotaxis and Ca2+ influx induced by eotaxin, RANTES, MCP-3 or MCP4, suggesting that most of the eosinophilic response to these chemokines in allergic and eosinophilic patients is mediated through CCR-3. See Heath, H. et al., J. Clin. Invest. (1997) 99, 178-184. Similarly, it has recently been disclosed that certain cyclic amine derivatives are antagonistic to CCR-3 and may be useful for treating eosinophil-mediated allergic diseases. See EP 0903349A2. Also, CCR-3 expression on human Th2 type T-cells and human cultured dendritic cells mediates cell functions such as chemotactic response. See Sallusto, F. et al., Science (1997) 277, 2005-2007; Sato, K. et al., Blood (1999) 93, 34-42. In addition, anti-CCR-3 antibody has been shown to inhibit aggregation of T-cells and dendritic cells, suggesting CCR-3 may regulate the interaction of these cells during the process of antigen presentation. See Sato, K. et al., Blood (1999) 93, 34-42. Therefore, CCR-3 inhibitors may also be useful for regulating immune responses.
These examples suggest that CCR-3 mediated diseases may be treated using compounds that inhibit CCR-3 activity. Because CCR-3 is present on many cell types, however, and is responsible for a variety of disease states, an arsenal of compounds which inhibit CCR-3 activity is required to treat CCR-3 mediated diseases effectively.